N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof

ABSTRACT

N2-arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No. 760,745 filed Jan. 19, 1977, now U.S. Pat. No. 4,066,773, which in turn is a continuation-in-part of the following applications:

Ser. No. 653,217 of Jan. 28, 1976, now U.S. Pat. No. 4,055,651; Ser. No. 713,486 of Aug. 11, 1976, now U.S. Pat. No. 4,073,914; Ser. No. 671,436 of Mar. 29, 1976, now U.S. Pat. No. 4,066,758; Ser. No. 703,704 of July 8, 1976, now U.S. Pat. No. 4,069,323. The Ser. No. 671,436 is a divisional of Ser. No. 622,390 filed Oct. 14, 1975 abandoned.

BACKGROUND OF THE INVENTION

Field of the Invention

This invention relates to the discovery of certain new and useful N² -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof, which are of especial value in view of their outstanding antithrombotic properties and low toxicities.

Description of the Prior Art

In the past, there have been many attempts to obtain new and improved agents for the treatment of thrombosis. The N² -(p-tolysulfonyl)-L-arginine esters have been found to be one type of agent which can be used and these have been found to be effective in dissolving blood clots. (U.S. Pat. No. 3,622,615, issued Nov. 23, 1971). One family of compounds which have been found to be particularly useful as highly specific inhibitors of thrombin for the control of thrombosis is the N² -dansyl-L-arginine ester or amide. (Our pending U.S. application Ser. No. 496,939, filed Aug. 13, 1974 now U.S. Pat. No. 3,978,045). However, there is a continuing need for a highly specific inhibitor of thrombin for the control of thrombosis, which exhibits lower toxicity.

SUMMARY OF THE INVENTION

It has now been discovered that N² -arylsulfonyl-L-argininamides exhibit antithrombotic activity and even lower toxicity levels at the same relative potencies, as compared with the N² -dansyl-L-arginine ester or amide. An N² -arylsulfonyl-L-argininamide having the formula (I): ##STR1## or a pharmaceutically acceptable salt thereof, wherein R is ##STR2## wherein R₁ is --COOR₃ wherein R₃ is hydrogen, C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl or 5-indanyl; each R₂ independently is hydrogen, C₁ -C₁₀ alkyl, phenyl, C₁ -C₅ alkoxy, C₂ -C₆ alkoxycarbonyl, or carboxy; n is an integer of 1 to 4, R₁ is substituted into the piperidine ring at the 2 or 3 position; and R₂ is substituted into the piperidine ring at the 2, 3, 4, 5, or 6 position;

and Ar is naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl and C₂ -C₂₀ dialkylamino, and at least one substituent selected from the group consisting of C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₀ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy, or mixtures thereof; naphthyl substituted with at least one C₁ -C₅ alkoxy and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ - C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof; naphthyl substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof; 5,6,7,8-tetrahydronaphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof; a C₉ -C₁₆ cycloalkylphenyl, C₁₀ -C₁₈ cycloalkylalkylphenyl, C₉ -C₁₆ cycloalkoxyphenyl, C₉ -C₁₆ cycloalkylthiophenyl, C₇ -C₁₂ aralkyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 1,2-methylenedioxyphenyl, 1,2-ethylenedioxyphenyl, chromanyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl, 1,2-trimethylenedioxyphenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl group, any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl, oxo and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof; a naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, as-indacenyl, s-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo (b) thienyl, isobenzothienyl, oxanthrenyl, thianthrenyl, dibenzofuranyl, dibenzothienyl, phenoxathiinyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl group, any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof, a phenyl which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof.

Also encompassed within this invention are pharmaceutically acceptable salts thereof. This invention also relates to a method for inhibiting activity and suppressing activation of thrombin in vivo in mammals which comprises administering to a mammal a pharmaceutically (antithrombotically) effective amount of an N² -arylsulfonyl-L-argininamide or the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to a group of N² -arylsulfonyl-L-argininamides of the formula (I): ##STR3## wherein R is ##STR4## wherein R₁ is --COOR₃ wherein R₃ is selected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C₆ -C₁₀ aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl, or the like, and 5-indanyl; each R₂ independently is hydrogen, alkyl of 1-10 (preferably 1-6) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, decyl or the like, phenyl, C₁ -C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like, C₂ -C₆ alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl or the like, or carboxyl; n is an integer of 1 to 4; R₁ is substituted into the piperidine ring at the 2 or 3 - position; and R₂ is substituted into the piperidine ring at the 2, 3, 4, 5, or 6 - position, and Ar is a naphthyl group substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, butyl or the like, and dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, dipropylamino or the like, and at least one substituent selected from the group consisting of alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy or the like, sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or the like, amino, alkylamino of 1- 10 (preferably 1-5) carbon atoms, such as methylamino, ethylamino, propylamino, butylamino or the like, mercapto, alkylthio or 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylamino or the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, such as acetyl, propionyl or the like, hydroxyalkyl of 1-10 (preferably 14 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like, and phenyl optionally substituted with at least one hydrocy and/or C₁ -C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like; a naphthyl group sustituted with at least one C₁ -C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like, and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino, ethylamino, propylamino, butylamino or the like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylamino or the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, such as acetyl propionyl or the like, hydroxyalkyl of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like, and phenyl optionally substituted with at least one hydroxy and/or C₁ -C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like; a napthyl group substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino, ethylamino, propylamino, butylamino or the like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylamino or the like, alkylcarbonyl or 2-10 (preferably 2-6) carbon atoms, such as acetyl, propionyl or the like, hydroxyalkyl of 1-10 (preferably 1-5) carbon atoms, such as hyroxmethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like, and phenyl optionally substituted with at least one hydroxy and/or C₁ -C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like; a 5,6,7,8-tetrahydronaphthyl group substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, butyl or the like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy or the like, sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino or the like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylamino or the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, such as acetyl, propionyl, or the like, hydroxyalkyl of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethyl 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like, and phenyl optionally substituted with at least one hydroxy and/or C₁ -C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like; a C₉ -C₁₆ cycloalkylphenyl, such as cyclopentylphenyl, cyclohexylphenyl, cyclooctylphenyl or the like, C₁₀ -C₁₈ cycloalkylalkylphenyl, such as cyclohexylmethylphenyl, (2-cyclohexylethyl)phenyl, (4-cyclohexylbutyl)phenyl, cyclooctylmethylphenyl or the like, C₉ -C₁₆ cycloalkyloxyphenyl, such as cylopentyloxyphenyl, cyclohexyloxyphenyl, cyclooctyloxyphenyl or the like, C₉ -C₁₆ cycloalkylthiophenyl, such as cyclopentylthiophenyl, cyclohexylthiophenyl, cyclooctylthiophenyl or the like, C₇ -c₁₂ aralkyl, such as benzyl, phenethyl or the like, 9,10-dihydrophenanthryl, 5,6,7,8-tetrahydroanthryl 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 1,2-methylenedioxphenyl, 1,2-ethylenedioxyphenyl, chromanyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl, 1,2-trimethylenedioxyphenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl, or 1,2,3,4-tetrahydroisoquinolyl group each of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, butyl or the like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy or the like, dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, dipropylamino or the like, sulfoamino, carbamoyl, N,N-dialkylcarbamoyl or 3-10 (preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino or the like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as mthoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylamino or the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, such as acetyl, propionyl, or the like, hydroxyalkyl of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like, oxo and phenyl optionally substituted with at least one hydroxy and/or C₁ -C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like; a naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, as-indacenyl, s-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo(b)thienyl, isobenzothienyl, oxanthrenyl, thianthrenyl, dibenzofuranyl, dibenzothienyl, phenoxathiinyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthyridinyl, quinoxalinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl group each of whih is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, butyl or the like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy or the like, dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, dipropylamino or the like, sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino, ethylamino, propylamino, butylamino or the like, mercapto, alkylthio of 1-10 (preferably 1-5 ) carbon atoms, such as methlthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl 2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylamino or the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, such as acetyl, propionyl or the like, hydroxyalkyl of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like, and phenyl optionally substituted with at least one hydroxy and/or C₁ -C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like; a phenyl which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, butyl or the like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy or the like, dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, dipropylamino or the like, sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino or the like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms, such as methylthio, ehtylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylamino or the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, such as acetyl, propionyl or the like, hydroxyalkyl of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like, and phenyl optionally substituted with at least one hydroxy and/or C₁ -C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like. Illustrative of suitable N² -arylsulfonyl-L-argininamides are those shown in the table below. In this table, the prior art reference cited in the second column discloses a method of preparation for the compound listed in the second column. The Example No listed in the last column refers to an Example of this application which discloses the details of a method by which the product compound of the fifth column of the table may be prepared.

    __________________________________________________________________________                                     Product                                         or salt thereofArSO.sub.2 CL or ArSO.sub.3 H                                                        Starting material                                                                         ##STR5##                   Pro-rationPrep                                                                a-                  No.                                                                               (Literature reference)                                                                           Amino acid ester                                                                          Ar             R           cedure              __________________________________________________________________________      1                                                                                 ##STR6##                                                                                         ##STR7##                                                                                  ##STR8##                                                                                      ##STR9##   1                      Ber., 54, 102 (1921)                                                         2                                                                                 ##STR10##                                                                                        ##STR11##                                                                                 ##STR12##                                                                                     ##STR13##  1                      CA, 25, 5420                                                                 3                                                                                 ##STR14##                                                                                        ##STR15##                                                                                 ##STR16##                                                                                     ##STR17##  1                      CA, 22, 413                                                                  4                                                                                 ##STR18##                                                                                        ##STR19##                                                                                 ##STR20##                                                                                     ##STR21##  1                      CA, 33, 4227                                                                 5                                                                                 ##STR22##                                                                                        ##STR23##                                                                                 ##STR24##                                                                                     ##STR25##  1                      Zhur Obshei Khim 18, 1459 (1948)                                             6                                                                                 ##STR26##                                                                                        ##STR27##                                                                                 ##STR28##                                                                                     ##STR29##  1                      Compt. rend 198, 2260 (1934)                                                 7                                                                                 ##STR30##                                                                                        ##STR31##                                                                                 ##STR32##                                                                                     ##STR33##  1                      Compt. rend 198, 2260 (1934)                                                 8                                                                                 ##STR34##                                                                                        ##STR35##                                                                                 ##STR36##                                                                                     ##STR37##  1                      J. Chem. Eng. Data 12, 610 (1967)                                            9                                                                                 ##STR38##                                                                                        ##STR39##                                                                                 ##STR40##                                                                                     ##STR41##  1                      J. Pharm. Soc. Japan 73 1878 (1953)                                         10                                                                                 ##STR42##                                                                                        ##STR43##                                                                                 ##STR44##                                                                                     ##STR45##  1                      J. Pharm. Soc. Japan 76, 103 (1958)                                         11                                                                                 ##STR46##                                                                                        ##STR47##                                                                                 ##STR48##                                                                                     ##STR49##  1                      U.S. 2,476,541                                                              12                                                                                 ##STR50##                                                                                        ##STR51##                                                                                 ##STR52##                                                                                     ##STR53##  1                      J.Pr. (2) 118, 75                                                           13                                                                                 ##STR54##                                                                                        ##STR55##                                                                                 ##STR56##                                                                                     ##STR57##  1                      Photophysik Photochem, 58, 3 (1963)                                         14                                                                                 ##STR58##                                                                                        ##STR59##                                                                                 ##STR60##                                                                                     ##STR61##  1                      J. Gen. Chem., 16, 1873                                                     15                                                                                 ##STR62##                                                                                        ##STR63##                                                                                 ##STR64##                                                                                     ##STR65##  1                      Ber. 86, 951 (1953)                                                         16                                                                                 ##STR66##                                                                                        ##STR67##                                                                                 ##STR68##                                                                                     ##STR69##  1                      Zhur Obschei Khim, 30, 1218 (1960)                                          17                                                                                 ##STR70##                                                                                        ##STR71##                                                                                 ##STR72##                                                                                     ##STR73##  1                      Bull. Soc. Chem. France, 1950, 466                                          18                                                                                 ##STR74##                                                                                        ##STR75##                                                                                 ##STR76##                                                                                     ##STR77##  1                      Bull. Soc. Chem. France, 1950, 466                                          19                                                                                 ##STR78##                                                                                        ##STR79##                                                                                 ##STR80##                                                                                     ##STR81##  1                      CA 62, 14675b                                                               20                                                                                 ##STR82##                                                                                        ##STR83##                                                                                 ##STR84##                                                                                     ##STR85##  1                      CA 26, 4723                                                                 21                                                                                 ##STR86##                                                                                        ##STR87##                                                                                 ##STR88##                                                                                     ##STR89##  1                      J. Am., Chem. Soc., 57, 1533 (1935)                                         22                                                                                 ##STR90##                                                                                        ##STR91##                                                                                 ##STR92##                                                                                     ##STR93##  1                      CA 45 9063i                                                                 23                                                                                 ##STR94##                                                                                        ##STR95##                                                                                 ##STR96##                                                                                     ##STR97##  1                      Org. Synth. II, 539                                                         24                                                                                 ##STR98##                                                                                        ##STR99##                                                                                 ##STR100##                                                                                    ##STR101## 1                      Beilstein 11, II 135                                                        __________________________________________________________________________

also illustrative of suitable N² -arylsulfonyl-L-argninamides are those shown in the table below. In this table, the Example No listed in the sixth column refers to the Example of this application by which the compound in the first column was prepared.

    Table 2       Compound       ##STR102##       Concentrationrequired toprolong thecoagulationtime by a Preparation      Elementary analysisUpper: Calculated (%) Sample  Addition factor of two      process m.p. Lower: Found (%) I.R. (KBr) No. Ar R moiety (μM) (Ex.      No.) (°       C) C H N (cm.sup.-1)                                                  1       ##STR103##       ##STR104##       -- 8 1 powder 52.7652.68 6.356.21 13.38 13.30 3,3603,1601,620  2 "       ##STR105##       1/2H.sub.2       SO.sub.3  1 134-6 52.2552.07 6.826.73 11.2910.89 3,3603,1801,7401,375      3 "       ##STR106##       -- 0.3 1 powder 53.6253.48 6.566.43 13.0312.98 3,3603,1401,622  4 "       ##STR107##       1/2H.sub.2       SO.sub.3  1 164-6 52.9852.69 7.006.98 11.0410.86 3,3903,1651,7351,370      5 "       ##STR108##       -- 2 1 powder 53.6253.43 6.566.51 13.0313.12 3,3603,160 1,620  6 "       ##STR109##       1/2H.sub.2       SO.sub.3  1 " 52.9852.59 7.006.79 11.0410.89 3,3903,1701,7871,370  7 "       ##STR110##       -- 5 1 " 54.4354.38 6.766.79 12.7012.56 3,3503,1801,630       8 "      ##STR111##       1/2H.sub.2       SO.sub.3  1 195-6 53.6953.40 7.157.12 10.8010.56 3,3803,1801,7381,375      9 "       ##STR112##       -- 1.5 1 powder 55.2154.98 6.957.02 12.3812.47 3,3603,200 1,622   10      "      ##STR113##       1/2H.sub.2                                                              1       SO.sub.3  1 198-200 54.3754.30 7.307.27 10.5710.36 3,3603,160,7301,368      11 "       ##STR114##       --  1 powder 56.6456.41 7.307.17 11.8011.51 3,3603,1801,620  12 "       ##STR115##       1/2H.sub.2                                                              1       SO.sub.3  1 172-174 55.6455.31 7.597.63 10.1410.18 3,3803,180,7401,375      13 "       ##STR116##       -- 0.5 3 powder 51.2050.93 6.176.02 12.9812.63 3,3803,1801,630  14 "       ##STR117##       ##STR118##       1.5 3 185 47.6747.64 4.924.81 11.1211.12 3,3753,2001,740       15 "      ##STR119##      -- 2.5 3 powder 52.0752.21 6.376.04 12.6712.51 3,3803,2001,620  16 "       ##STR120##       --  3 " 53.6953.53 6.766.69 12.0412.35 3,3803,2001,740       17 "      ##STR121##       -- 2.5 1 " 52.9052.71 6.576.43 12.3412.46  3,3503,1601,640  18 "       ##STR122##       1/2H.sub.2       SO.sub.3  1 " 52.4052.16 6.967.13 10.5410.28 3,3403,1601,7361,380  19 "       ##STR123##       -- 5 1 " 52.0751.91 6.376.19 12.6512.38 3,3603,1601,620       20 "      ##STR124##       1/2H.sub.2       SO.sub.3  1 " 51.6851.43 6.826.66 10.7610.58 3,3803,1601,7401,370  21 "       ##STR125##       -- 4 1 " 52.9052.59 6.57 6.41 12.3412.16 3,3603,1601,640       22 "      ##STR126##       1/2H.sub.2       SO.sub.3  1 " 52.9852.73 7.007.00 11.0410.82 3,3773,1601,7401,368  23       ##STR127##       ##STR128##       -- 4 4 " 51.2051.31 6.176.01 12.9812.67 3,3603,1801,610       24 "      ##STR129##       ##STR130##        4 225-7 47.6747.62 4.924.84 11.1211.18 3,3753,2001,742       25 "      ##STR131##       -- 2 1 powder 53.6253.58 6.566.48 13.0312.94 3,3803,2001,630  26 "       ##STR132##       1/2H.sub.2                                                              1       SO.sub.3  1 224 52.9852.73 7.007.00 11.0410.823,3603,1601,740,370  27       ##STR133##       ##STR134##       -- 15 1 powder 52.8952.77 6.576.80 12.3412.59 3,3803,2001,625  28 "       ##STR135##       1/2H.sub.2                                                              1       SO.sub.3  1 " 52.3952.10 6.976.84 10.5410.21  3,3703,1501,740,370  29 "       ##STR136##       --  1 " 55.2055.00 6.956.81 12.3812.21 3,3603,1501,620       30 "      ##STR137##       1/2H.sub.2       SO.sub.3  1 " 54.3654.25 7.307.11 10.5710.813,3703,2001,7351,370  31       ##STR138##       ##STR139##       -- 0.5 1 " 54.4354.21 6.556.50 13.8013.79 3,3603,1801,632  32 "       ##STR140##       1/2H.sub.2                                                              1       SO.sub.3  1 " 53.6353.50 7.006.79 11.58 11.40 3,3803,2001,740,370  33 "       ##STR141##       --  1 " 51.8651.64 6.136.09 13.7513.84 3,3703,2001,625       34 "      ##STR142##       1/2H.sub.2       SO.sub.3  1 " 55.2155.11 6.956.76 12.5812.27 3,3803,1801,7381,368  35       ##STR143##       ##STR144##       -- 0.5 3 " 51.8651.72 6.136.11 13.7513.63 3,3703,1601,620  36 "       ##STR145##       ##STR146##        3 158-160 47.9447.83 4.854.80 11.5111.43 3,3753,2001,740  37 "       ##STR147##       --  1 powder 53.5353.40 6.336.21 14.1914.04 3,3753,1501,620  38 "       ##STR148##       1/2H.sub.2       SO.sub.3  1 " 52.8652.77 6.836.66 11.8611.75 3,3803,2001,7401,370  39 "       ##STR149##       -- 0.5 1 " 54.4354.22 6.556.31 13.8013.59 3,3803,1501,620  40 "       ##STR150##       1/2H.sub.2 SO.sub.3  1 131-137(dec.) 53.6353.40 7.007.10 11.5811.40      3,3803,1601,7501,640       41 "      ##STR151##       --  1 powder 55.2655.21 6.766.65 13.4313.29 3,3501,630       42 "      ##STR152##       1/2H.sub.2 SO.sub.3  1 169-175(dec.) 54.3554.27 7.177.00 11.3211.08      3,3503,1801,7401,640 43       ##STR153##       ##STR154##       -- 2.5 1 powder 51.8651.77 6.136.00 13.7513.72 3,3653,2001,620  44 "       ##STR155##       1/2H.sub.2       SO.sub.3  1 " 51.4751.20 6.656.35 11.5411.24 3,3703,2003,3401,370  45 "       ##STR156##       --  1 " 54.4354.28 6.556.31 13.8013.70 3,3753,2001,622       46 "      ##STR157##       1/2H.sub.2       SO.sub.3  1 " 53.6353.53 7.007.08 11.5811.40 3,3803,2001,7401,370  47 "       ##STR158##       --  1 " 52.7652.47 6.356.01 13.3813.09 3,3753,1801,620       48 "      ##STR159##       1/2H.sub. 2                                                             1       SO.sub.3  1 " 52.2452.00 6.826.55 11.2811.00 3,3803,2001,740,368  49       ##STR160##       ##STR161##       0.5 H.sub.2 SO.sub.3  1 189-191(dec.) 55.6855.36 6.336.35 10.4710.45      3,3603,160s1,730       50 "      ##STR162##       -- 2.5 1 powder 56.7356.43 5.825.80 12.2512.19 3,3703,2001,615  51  "       ##STR163##       ##STR164##        1 132-135(dec.) 52.7852.61 5.17 5.15 10.2610.23 3,3603,1831,720  52 "       ##STR165##       -- 10 1 powder 57.4257.19 6.02 6.10 11.9611.73 3,3603,1601,620  53 "       ##STR166##       ##STR167##        1 157-158(dec.) 52.7852.63 5.175.14 10.2610.09 3,3803,2201,750  54 "       ##STR168##       -- 3.0 1 powder 57.4257.09 6.026.06 11.9611.74 3,3603,2001,590  55 "       ##STR169##       ##STR170##        1 155-157(dec.) 53.2553.13 5.305.21 10.1110.03 3,3803,1801,720  56 "       ##STR171##       -- 50 1 powder 58.0857.93 6.226.04 11.6811.54 3,200-3,380(broad)1,620      57       ##STR172##       ##STR173##       ##STR174##        1 153-156(dec.) 52.2852.14 5.034.98 10.4110.36 3,4003,0801,740  58 "       ##STR175##       -- 6.5 1 powder 56.7356.58 5.825.73 12.2512.14 3,000-3,400(broad)1,600      59       ##STR176##       ##STR177##       ##STR178##        1 144-148(dec.) 53.6753.69 5.265.24 10.4310.39 3,3603,2001,720  60 "       ##STR179##       -- 50 1 powder 59.0459.14 6.196.15 12.3012.28 3,040-3,360(broad)1,610      61 "       ##STR180##       ##STR181##        1 155-158(dec.) 53.1954.97 5.125.06 10.5910.48 3,4003,2001,730  62 "       ##STR182##       -- 15 1 powder 58.3758.19 6.005.98 12.6112.49 3,300(broad)1,640  63       ##STR183##       ##STR184##       ##STR185##        1 147-150(dec.) 59.1959.23 5.125.07 10.5910.54 3,4003,2301,750  64 "       ##STR186##       -- 20 1 powder 58.3758.21 6.005.93  12.6112.46 3,200(broad)1,620  65       ##STR187##       ##STR188##       --  1 " 60.2960.21 6.586.56 11.7211.643,3653,1701,730       66 "      ##STR189##       -- 2.0 1 " 57.6657.48 5.775.74 12.9312.84 3,3603,1601,610       67      ##STR190##       ##STR191##       -- 1 1 " 50.2550.45 5.956.01 13.3213.15 3,3501,6201,3801,150  68       ##STR192##       ##STR193##       1/2H.sub.2       SO.sub.3  1 " 50.4350.57 6.656.58 10.5010.71 3,3501,7451,6501,360  69 "       ##STR194##       -- 5 1 171-2 50.6050.51 6.196.30 12.2912.40 3,4001,6351,2601,160  70 "       ##STR195##       --  2 powder 55.4055.65 6.626.81 12.4312.19 3,2201,7501,640  71       ##STR196##       ##STR197##       -- 5 2 " 53.8253.66 6.215.96 13.0812.81 3,3501,6251,155       72      ##STR198##       ##STR199##       ##STR200##        2 192-193 49.5849.24 4.874.70 11.5611.85 3,2101,7471,638  73 "       ##STR201##       -- 3 2 powder 54.6456.88 6.186.31 13.8513.83 3,200 (broad)1,6201,150      74       ##STR202##       ##STR203##       -- 0.4 2 " 54.6354.50 6.426.09 12.7412.81 3,3701,6251,158 75       ##STR204##       ##STR205##       ##STR206##        2 188-190 50.1750.01 5.034.78 11.3811.56 3,2001,7401,635 76       ##STR207##       ##STR208##       -- 0.15 2 powder 55.4755.49 6.406.33 13.9813.51 3,250 (broad)1,625 77       ##STR209##       ##STR210##      --  2 " 57.0256.81 6.816.91 12.7912.78 3,2001,7401,635 78 "       ##STR211##       --  2 " 55.4755.31 6.406.68 13.4813.21 3,3501,6201,150       79      ##STR212##       ##STR213##       ##STR214##        2 222-3 49.8249.57 5.094.88 11.9911.68 3,2001,7451,630       80 "      ##STR215##       -- 0.35 2 powder 54.6354.55 6.426.42 12.7412.58 3,350 (broad)1,6201,150       81      ##STR216##       ##STR217##       ##STR218##        2 154-6 50.92 51.28 5.375.21 10.6610.59 3,4001,7351,635       82 "      ##STR219##       --  2 powder 56.1356.11 6.806.85 12.1211.95 3,300 (broad)1,6101,255  83       ##STR220##       ##STR221##       ##STR222##        2 179-180 50.3850.34 5.235.18 10.8211.05 3,3801,7351,635  84 "       ##STR223##       --  2 powder 55.4055.71 6.626.48 12.4312.53 3,3601,6201,150  85 "       ##STR224##       ##STR225##        2 125(soften) 50.7350.58 5.185.11 11.1910.93 3,3801,7351,638  86 "       ##STR226##       --  2 powder 56.2656.41 6.616.48 13.1213.27 3,3601,6201,158  87       ##STR227##       ##STR228##      --  2 " 57.5057.56 7.157.08 11.5611.71 3,3302,9601,7401,640  88 "       ##STR229##       -- 0.5 2 " 56.1356.11 6.806.81 12.1211.96 3,4001,620       89 "      ##STR230##       --  2 " 57.5057.15 7.157.21 11.5611.62 3,3602,9601,735       90 "      ##STR231##       --  2 " 56.1356.21 6.806.81 12.1212.03 3,4001,6201,150       91 "      ##STR232##       --  2 " 54.6354.54 6.426.40 12.7412.68 3,3501,6201,150       92 "      ##STR233##      --  2 " 56.1356.08 6.806.91 12.1212.08 3,2501,7401,640       93      ##STR234##       ##STR235##       --  2 " 57.0256.86 6.816.83 12.7912.68 3,2301,7401,650       94 "      ##STR236##       --  2 " 54.6354.59 6.426.38 12.7412.68 3,2501,6201,160       95      ##STR237##       ##STR238##       ##STR239##        2 161-163 48.9749.05 4.714.73 11.7611.58 3,3401,7381,635  96 "       ##STR240##       --  2 powder 53.8253.68 6.216.08 13.0812.85 3,3701,6351,2551,155  97       ##STR241##       ##STR242##       --  2 " 54.6454.58 6.186.09 13.8519.93 3,3701,6401,2601,155  98       ##STR243##       ##STR244##       ##STR245##        1 165-168(dec.) 51.9451.50 5.645.41 10.3410.40 3,3903,2201,740 99 "       ##STR246##       --  1 powder 56.13 56.00 6.816.73 12.1212.01 3,350 (broad)1,640  100 "       ##STR247##       ##STR248##        1 178-181(dec.) 51.9452.24 5.645.60 10.3410.28 3,4003,2001,735  101 "       ##STR249##       --  1 powder 56.1356.28 6.816.59 12.1212.31 3,350 (broad)1,640  102       ##STR250##       ##STR251##       ##STR252##        1 162-165(dec.) 51.4351.28 5.505.21 10.5010.21 3,3703,2001,730  103 "       ##STR253##      --  1 powder 55.4055.28 6.626.32 12.4312.03 3,300 (broad)1,610 (broad)      104       ##STR254##       ##STR255##       ##STR256##        1 158-160(dec.) 52.7552.56 5.565.43 11.0410.97 3,4053,2201,740  105 "       ##STR257##       --  1 powder 56.2656.01 6.616.49 19.1813.21 3,320 (broad)1,640  106       ##STR258##       ##STR259##       ##STR260##        1 160-163(dec.) 52.3352.03 5.605.30 10.6810.28 3,4003,2101,730  107 "       ##STR261##      --  1 powder 57.0257.39 6.816.21 12.7912.38 3,350(broad)1,620  108       ##STR262##       ##STR263##       ##STR264##        1 152-155(dec.) 52.8352.53 5.735.72 10.5210.29 3,3903,2051,730  109 "       ##STR265##       --   1 powder 57.7357.51 7.007.23 12.4712.28 3,3701,630       110      ##STR266##       ##STR267##       ##STR268##        1 170-172(dec.) 51.4351.09 5.505.45 10.5010.28 3,3803,2201,740  111 "       ##STR269##       -- 5 1 powder 55.4055.30 6.626.28 12.4312.11 3,2003,400 (broad)1,600      112 "       ##STR270##       ##STR271##        1 155-158 (dec.) 51.9452.29 5.645.63 10.3410.00 3,3803,2001,730 113 "       ##STR272##       --  1 powder 56.1356.40 6.816.61 12.1212.00 3,200-3,400(broad)1,600      114 "       ##STR273##       --  1 " 54.6354.40 6.426.30 12.7412.50 3,200-3,400(broad)1,600  115 "       ##STR274##       ##STR275##        1 165-170(dec.) 50.8150.68 5.585.43 10.64 10.31 3,3803,2001,740  116 "       ##STR276##       --  1 powder 54.4354.70 6.766.71 12.7012.35 3,4001,590       117 "      ##STR277##       ##STR278##        1 164-166 51.3351.60 5.715.38 10.4810.25 3,3603,2001,735  118 "       ##STR279##       -- 2.0 1 powder 55.2155.00 6.956.30 12.3812.40 3,400-3,200(broad)1,570      119 "       ##STR280##       ##STR281##        1 168-172 52.7752.54 5.174.98 10.2610.21 3,3803,1801,740       120      ##STR282##       ##STR283##       -- 2.5 1 powder 57.4257.35 6.025.84 11.9612.00 3,350-1,160(broad)1,600      121 "       ##STR284##       ##STR285##        1 130-135 53.2553.08 5.305.29 10.1110.29 3,4003,2001,730  122 "       ##STR286##       -- 1.5 1 powder 58.0857.84 6.226.13 11.6811.46 3,3603,1601,600  123 "       ##STR287##       ##STR288##        1 158-163(dec.) 51.9551.80 5.645.38 10.3410.30 3,3603,2001,740  124 "       ##STR289##       --  1 powder 56.1455.98 6.816.79 12.1312.35 3,380-3,200(broad)1,625      125       ##STR290##       ##STR291##       ##STR292##        1 160-163(dec.) 52.4452.39  5.765.58 10.1910.00 3,4003,2001,740  126 "       ##STR293##       -- 4.5 1 powder 56.8456.72 6.996.80 11.8411.76 3,380-3,250(broad)1,595      127       ##STR294##       ##STR295##       ##STR296##        1 160-165(dec.) 50.6250.39 5.405.28 11.1711.15 3,4003,2101,740  128 "       ##STR297##       --  1 powder 54.4354.27 6.556.28 13.8013.59 3,2801,590       129      ##STR298##       ##STR299##       -- 5 1 " 52.0751.89 6.376.39 12.6512.51 3,3603,200 1,600       130      ##STR300##       ##STR301##       -- 20 5 210-213 54.8654.72 7.337.21 14.5414.27 3,3501,630       131      ##STR302##       ##STR303##       --  5 120-130 55.7355.82 7.527.50 14.1314.01 3,3501,630       132      ##STR304##       ##STR305##       -- 10 5 108-110 52.1552.21 6.886.71 14.4814.52 3,300 (broad)1,630  133       ##STR306##       ##STR307##       -- 30 5 powder 58.2358.01 6.456.35 13.5813.46 3,300 (broad)1,635  134       ##STR308##       ##STR309##       --  5 " 58.9658.91 6.666.79 13.2213.15 3,200 (broad)1,635       135      ##STR310##       ##STR311##       --  5 " 55.7355.81 7.527.40 14.1314.10 3,300 (broad)1,630  136 "       ##STR312##       --  5 170-173 57.5657.41 7.547.39 13.4313.50 3,3351,630       137      ##STR313##       ##STR314##       --  5 powder 56.7856.85 7.357.29 13.8013.71 3,200 (broad)1,630  138       ##STR315##       ##STR316##       --  5 " 58.9658.79 6.666.51 13.2213.19  3,300 (broad)1,630  139       ##STR317##       ##STR318##       --  5 142-145 49.0748.90 5.495.38 13.6313.42 3,1501,620       140      ##STR319##       ##STR320##       --  5 powder 47.4747.29 5.435.31 12.5812.39 3,1501,630       141      ##STR321##       ##STR322##       --  5 " 49.0749.12 5.495.28 13.6313.59 3,1501,630       142      ##STR323##       ##STR324##       --  5 123-130 57.0156.88 6.986.71 13.8513.65 3,3001,635       143      ##STR325##       ##STR326##       -- 0.3 5 powder 56.1956.00 6.776.50 14.2514.00 3,3003,1501,630  144 "       ##STR327##       -- 0.2 5 " 53.5353.24 6.336.19 14.1913.99 3,300 (broad)1,630  145 "       ##STR328##       --  5 " 60.0959.79 6.166.02 12.9312.61 3,300(broad)1,630  146 "       ##STR329##       -- 14 5 " 58.7358.66 7.016.90 13.1712.91 3,3801,635       147      ##STR330##       ##STR331##       --  5 147-150 52.5952.31 6.106.01 14.6114.33 3,3801,640       148 "      ##STR332##       --  5 powder 57.2356.98 6.616.33 13.9113.81 3,300(broad)1,630  149       ##STR333##       ##STR334##       --  5 " 58.6958.79 5.715.55 13.6913.39 3,300(broad)3,1501,630  150 "       ##STR335##       --  5 " 56.1955.95 6.776.58 14.2513.97 3,190(broad)1,620       151      ##STR336##       ##STR337##       -- 20 5 130-135 53.5353.28 6.336.19 14.1913.97 3,3501,640       152      ##STR338##       ##STR339##       -- 10 5 152-157 54.4254.28 6.556.32 13.8013.59 3,3501,635       153      ##STR340##       ##STR341##       -- 4 5 powder 55.3655.10 6.976.76 16.1416.07 3,3801,630       154 "      ##STR342##       --  5 " 52.8652.71 6.566.29 16.0816.07       155      ##STR343##       ##STR344##       --  5 " 50.9050.81 5.905.70 14.1313.89 3,180(broad)1,630       156      ##STR345##       ##STR346##       --  5 " 59.4159.22 5.955.73 13.3313.28 3,170(broad)1,620  157 "       ##STR347##       HCl  6 " 53.1752.89 6.696.52 12.9212.74       158 "      ##STR348##       HCl  6 " 57.6657.31 6.346.14 11.5911.16       159 "      ##STR349##       --  5 " 55.3355.26 6.546.62 14.6714.58 3,200(broad)1,630       160      ##STR350##       ##STR351##       -- 0.25 1 " 55.4755.75 6.406.19 13.4813.26 3,350(broad)1,6301,380  161      "       ##STR352##       -- 0.2 5 " 55.0555.28 7.127.00 13.3813.12 3,200(broad)1,6351,380  162       ##STR353##       ##STR354##       -- 0.2 1 " 54.2253.98 5.505.55 13.1813.24 3,320(broad)1,6301,380  163 "       ##STR355##       --  1 " 57.2257.23 6.356.36 11.9212.08 3,400(broad)1,7401,620  164 "       ##STR356##       -- 0.15 1 " 53.8253.78 6.216.19 13.0812.86 3,360(broad)1,6251,380  165      "       ##STR357##       --  1 " 56.8356.95 6.986.83 11.8411.98 3,400(broad)1,7351,630  166       ##STR358##       ##STR359##       CH.sub.3 CO.sub.2       H  5 " 53.2853.13 6.626.82 13.8113.71 3,320(broad)1,6301,140  167       ##STR360##       ##STR361##       --  5 " 51.1550.86 5.605.66 12.9712.87 3,320(broad)1,6301,380  168       ##STR362##       ##STR363##       --  5 " 54.6453.36 6.186.00 13.8513.58 3,350(broad)1,6401,390  169       ##STR364##       ##STR365##       --  5 " 56.2755.98 6.616.78 13.1213.24 3,350(broad)1,6301,3801,140  170       ##STR366##       ##STR367##       --  5 " 54.2154.36 6.926.93 13.7413.76 3,300(broad)1,6251,3821,160  171       ##STR368##       ##STR369##       --  1,2 " 53.0852.86 6.246.33 12.3812.41 3,300(broad)1,6401,160  172 "       ##STR370##       --  1 " 56.0255.83 6.976.88 11.2711.28  3,400(broad)1,7451,620  173       ##STR371##       ##STR372##       -- 0.2 3 " 57.2356.89 6.616.50 13.9113.70 3,390(broad)1,625  174 "       ##STR373##       CH.sub.3       COOH  3 " 56.8356.72 6.986.81 11.8411.56 3,400(broad)1,7351,640  175 "       ##STR374##       -- 0.1 2 " 58.7358.52 7.016.77 13.1713.00 3,380(broad)1,620  176       ##STR375##       ##STR376##       1/2H.sub.2       SO.sub.3  2 " 55.98 55.69 7.057.21 11.6611.38 3,400(broad)1,7301,635      177       ##STR377##       ##STR378##       --  3 " 58.7358.81 7.027.03 13.1713.17 3,300(broad)1,6151,380  178 "       ##STR379##       CH.sub.3       COOH  3 " 58.1357.98 7.327.56 11.3011.28 3,380(broad)1,7301,630  179       ##STR380##       ##STR381##       -- 1 3 " 56.4256.38 6.386.52 14.3114.53 3,350(broad)1,6201,160  180 "       ##STR382##       CH.sub.3       COOH  3 " 56.1356.08 6.806.83 12.1212.12 3,400(broad)1,7401,630  181       ##STR383##       ##STR384##       -- 0.5 3 " 58.0057.83 6.826.77 13.5013.63  3,350(broad)1,6201,160  182      "       ##STR385##       CH.sub.3       COOH  3 " 57.5057.61 7.157.11 11.5611.81 3,350(broad)1,7301,620  183       ##STR386##       ##STR387##       -- 0.35 3 " 55.5855.62 6.616.81 16.2116.03 3,350(broad)1,6201,140  184       ##STR388##       ##STR389##       --  3 " 55.9656.12 7.157.28 14.1914.07 3,350(broad)1,6201,150  185 "       ##STR390##       CH.sub.3       COOH  3 " 55.7455.90 7.457.51 12.0412.18 3,400(broad)1,7301,625  186       ##STR391##       ##STR392##       --  3 " 54.3854.08 6.215.91 12.6912.39 3,300(broad)1,625       187      ##STR393##       ##STR394##       --  2 " 52.2552.36 6.035.98 12.7012.51 3,4001,7351,6401,160  188 "       ##STR395##       --  2 " 50.4650.61 5.585.63 13.3813.40 3,3801,6201,3801,155  189 "       ##STR396##       -- 2 3 " 52.0652.31 5.765.81 13.8013.51 3,3201,6201,3901,155  190 "       ##STR397##       --  2 " 48.9649.13 5.425.38 12.9812.75 3,3501,6201,3801,150  191       ##STR398##       ##STR399##       -- 5 2 " 51.3851.45 5.815.86 13.0313.12  3,3501,6301,2551,150  192       ##STR400##       ##STR401##       --  2 " 49.5049.31 5.345.40 13.7513.68 3,3503,2001,622       193      ##STR402##       ##STR403##       --  2 " 58.2758.45 5.906.03 11.7211.53 3,3501,7401,6401,2601,160  194 "       ##STR404##       -- 2 2 " 57.6257.68 5.705.55 12.0011.73 3,300(broad)1,6201,2501,150      195 "       ##STR405##       -- 1.5 3 "  56.9357.12 5.495.43 12.3012.14 3,3601,6251,2601,150  196 "       ##STR406##       -- 6.5 1 " 54.6354.28 6.426.31 12.7412.53 3,350(broad)1,740  197 "       ##STR407##       --  2 " 53.8654.16 5.925.62 13.0012.70 3,100(broad)1,620  198 "       ##STR408##       1/2 H.sub.2       SO.sub.3  2 " 54.5354.23 6.105.80 9.649.34 1,720(broad)1,630  199       ##STR409##       ##STR410##       --  2 " 48.5548.31 4.934.64 11.8011.53 3,300(broad)1,620       200      ##STR411##       ##STR412##       HCl 2 6 " 54.1053.81 7.327.13 10.18 9.93 3,180(broad)1,7401,630  201 "       ##STR413##       --  2 " 57.2256.98 6.246.18 11.1211.31 3,3001,1501,7401,650  202 "       ##STR414##       HCl 20 6 " 54.0953.83 6.055.97 10.5110.36 3,2503,1001,7401,640  203 "       ##STR415##       HCl 30 6 " 55.5355.37 6.126.01 10.1210.01 3,3503,1501,7401,650  204       ##STR416##       ##STR417##       -- 4.5 2 " 48.9649.13 5.425.36 12.9813.01 3,3501,6201,380  205 "       ##STR418##       -- 2.5 2 " 54.6454.63 6.426.56 12.7413.01 3,3602,9401,6201,380  206       ##STR419##       ##STR420##       -- 12 2 " 59.8959.65 4.524.63 11.6411.81 3,3601,6201,2551,150  207 "       ##STR421##       -- 55 2 "  50.1549.91 6.416.35 14.0413.83 3,2801,620       208 "      ##STR422##       --  2 " 53.8553.61 5.935.76 13.0012.84 3,3201,610       209 "      ##STR423##       -- 2 2 " 57.4257.37 6.025.86 11.9611.74 3,300(broad)1,600       210      ##STR424##       ##STR425##       --  2 " 57.4157.33 6.035.94 11.9611.73 3,3001,610 211 "       ##STR426##       -- 2.52 " 53.9853.74 5.385.33 11.6611.743,3501,630       212      ##STR427##       ##STR428##       -- 6.5 2 "52.0652.40 6.386.37 12.6512.73 3,350(broad)1,620  213 "       ##STR429##       --  2 " 52.0751.95 6.376.27 12.6512.84 3,350(broad)1,620  214 "       ##STR430##       -- 15 2 " 52.7552.68 6.366.34 13.3813.41 3,380(broad)1,620  215 "       ##STR431##       --  2 " 50.9750.67 6.586.61 13.7213.39 3,200(broad)1,610(broad)  216 "       ##STR432##       1/2H.sub.2 SO.sub.3  2 " 52.0151.77 6.696.50 10.1110.00 1,7251,620  217       ##STR433##       ##STR434##       --  5 " 46.8146.63 6.005.94 14.3714.23 3,4003,3001,630       218      ##STR435##       ##STR436##       --  5 " 51.3851.24 5.825.79 13.0312.87 3,3803,3001,630       219      ##STR437##       ##STR438##       --  1 "  52.1552.03 6.886.73 14.4814.68 3,3551,6301,3801,305  220       ##STR439##       ##STR440##       2H.sub.2 O 2 2 195-198 50.4250.48 6.546.16 12.2512.31 3,3201,620  221 "       ##STR441##       1/2H.sub.2 O 15 2 229-233 52.9452.73 6.306.15 12.8712.93 3,3501,620      222       ##STR442##       ##STR443##       -- 6.5 1 powder 48.7848.54 5.775.76 12.9313.15 3,3201,6201,390  223       ##STR444##       ##STR445##       --  1 " 50.2750.11 5.955.87 13.3313.34 3,3901,6301,2601,160  224       ##STR446##       ##STR447##       --  5 " 53.7653.66 5.955.83 14.2514.19 3,4003,2001,635       225      ##STR448##       ##STR449##       --  5 " 46.6246.53 6.386.21 14.3114.43 3,3503,1501,630       226      ##STR450##       ##STR451##       --  5 " 49.7149.84 7.027.26 13.1813.36 3,250broad 3,1501,630  227 "       ##STR452##       --  5 " 46.2446.31 6.406.53 13.4813.41 3,3203,1501,630       228      ##STR453##       ##STR454##       HCl  1 " 47.7447.53 6.756.51 14.6514.41 3,3403,1801,640       229      ##STR455##       ##STR456##         1  52.9552.79 6.005.87 13.4313.28 3,3503,1501,620       230 "      ##STR457##         1  53.16 5.64 13.48       231      ##STR458##       ##STR459##         5  40.7140.60 4.954.78 13.1913.03 3,3603,1601,620       232      ##STR460##       ##STR461##       --  3 " 55.5955.54 6.296.14 12.4712.35 3,3503,1501,625       233      ##STR462##       ##STR463##       --  3 " 57.4357.26 6.136.04 12.8812.71 3,3503,1301,615       234      ##STR464##       ##STR465##       --  5 " 46.8046.61 6.116.05 15.1615.23 3,3753,1501,630       235      ##STR466##       ##STR467##       --  3 " 50.8250.71 6.866.69 12.8912.57 3,3603,1201,620

The pharmaceutically acceptable salts of the above compounds are of course also included within the scope of this invention.

For the preparation of the compounds of this invetion, various methods can be employed depending upon the particular starting materials and/or intermediates involved. Successful preparation of these compounds is possible by way of several synthetic routes which are outlined below.

(a) Condensation of an L-argininamide with an arylsulfonyl halide. This process may be illustrated as follows: ##STR468## In the above formulas, R and Ar are as defined herein above; X is halogen; R'" is a protective group for the α-amino group, such as benzyloxycarbonyl or tertbutoxycarbonyl; R' and R" are selected from the group consisting of hydrogen and protective groups for the guanidino group, such as nitro, tosyl, trityl, oxycarbonyl and the like; and at least one of R' and R" is a protective group for the guanidino group. The N² -arylsulfonyl-L-argininamide (I) is prepared by the condensation of an L-argininamide (VI) with a substantially equimolar amount of an arylsulfonyl halide (VII), preferably a chloride.

The condensation reaction is generally effected in a suitable reaction-inert solvent in the presence of an excess of a base, such as an organic base (triethylamine, pyridine) or a solution or an inorganic base (sodium hydroxide, potassium carbonate), at a temperature of 0° C to the boiling temperature of the solvent for a period of 10 minutes to 15 hours.

The preferred solvents for the condensation include benzene-diethyl ether, diethyl ether-water and dioxane-water.

After the reaction is complete, the formed salt is extracted with water, and the solvent is removed by such standard means as evaporation under reduced pressure to give the N² -arylsulfonyl-L-argininamide (I), which can be purified by trituration or recrystallization from a suitable solvent, such as diethyl ethertetrahydrofuran, diethyl ether-methanol and water-methanol, or may be chromotographed on silica gel. The L-argininamides (VI) starting materials required for the condensation reaction can be prepared by protecting the guanidino and α-amino groups of L-arginin (II) via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzyloxycarbonylation, benzolylation, benzyloxycarbonylation, tert-butoxycarbonylation or tritylation and then condensing the formed N^(G) -substituted-N² -substituted-L-arginine (III) with a corresponding amino acid derivative (IV) by such a conventional process as the acid chloride method, azide method, mixed anhydride method, activated ester method or carbodiimide method, and thereafter selectively removing the protective groups from the formed N^(G) -substituted-N² -substituted-L-argininamide (V).

The amino acid derivatives (IV) which are the starting materials for the preparation of the N^(G) -substituted-N² -substituted-L-argininamides (V) are represented by the following formula (VIII). ##STR469## In the above formulas, R₁, R₂ and n are as defined herein above.

accordance with the process employed for preparing 2-piperidinecarboxylic acid derivatives (VIII),the following scheme is illustrative: ##STR470## In the first reaction of the aforementioned scheme, an appropriately substituted piperidine (IX) is contacted with an aqueous sodium hypochlorite solution at a temperature of -5° C to 0° C. The resultant product (X) is isolated by extraction with solvent, e.g., diethyl ether, and then treated with potassium hydroxide in a lower alkanol solvent to give the 1,2-dehydropiperidine (XI). The action of cyanogenating agents, e.g., hydrogen cynaide or sodium cyanide converts the 1,2-dehydropiperidines (XI) to the corresponding 2-cyano analogs (XII). Hydrolysis of the 2-cyanopiperidines (XII) to yield the 2-piperidinecarboxylic acids (XIII) is effected by treatment of the 2-cyanopiperidines (XII) with an inorganic acid, such as hydrochloric acid or sulfuric acid.

The arylsulfonyl halides (VII) which are the starting materials for the preparation of the N² -arylsulfonyl-L-argininamides (I) can be prepared by halogenating the requisite arylsulfonic acids or their salts, e.g., sodium salts, by conventional methods well known to those skilled in the art.

In practice, halogenation is carried out without a solvent or in a suitable solvent e.g., halogenated hydrocarbons or DMF in the presence of a halogenating agent, e.g., phosphorous oxychloride, thionyl chloride, phosphorous trichloride, phosphorous tribromide or phosphorous pentachloride, at a temperature of -10° C to 200° C for a period of 5 minutes to 5 hours. After the reaction is complete, the reaction product is poured into ice water and then extracted with a solvent such as ether, benzene, ethyl acetate, chloroform or the like.

The arylsulfonyl halide can be purified by recrystallization from a suitable solvent such as hexane, benzene or the like.

(b) Removal of the N^(G) -substituent from an N^(G) -substituted-N² -arylsulfonyl-L-argininamide

This process may be illustrated as follows: ##STR471## In the above formulas, R, Ar, X, R', R" and R'" are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by removing the N^(G) -substituent from an N^(G) -substituted-N² -arylsulfonyl-L-argininamide (XV) by means of acidolysis or hydrogenolysis.

The acidolysis is generally effected by contacting the N^(G) -substituted-N² -arylsulfonyl-L-argininamide (XV) and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without a solvent or in a solvent, such as an ether (tetrahydrofuran, dioxane), an alcohol (methanol, ethanol) or acetic acid at a temperature of -10° C to 100° C, and preferably at room temperature for a period of 30 minutes to 24 hours.

The products are isolated by evaporation of the solvent and the excess acid, or by trituration with a suitable solvent followed by filtration and drying.

Because of the use of the excess acid, the products are generally the acid addition salts of the N² -arylsulfonyl-L-argininamides (I), which can be easily converted to a free amide by neutralization.

The removal of the nitro group and the oxycarbonyl group, e.g., benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is readily accomplished by the hydrogenolysis. At the same time, the benzyl ester moiety which can be included in the R group is converted to the carboxyl group by the hydrogenolysis.

The hydrogenolysis is effected in a reaction-inert solvent, e.g., methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen-activating catalyst, e.g., Raney nickel, palladium, or platinum, in a hydrogen atmosphere at a temperature of 0° C to the boiling temperature of the solvent for a period of 2 hours to 120 hours.

The hydrogen pressure is not critical, and atmospheric pressure is sufficient.

The N² -arylsulfonyl-L-argininamides (I) are isolated by filtration of the catalyst followed by evaporation of the solvent.

The N² -arylsulfonyl-L-argininamides can be purified in the same manner as described above.

The N^(G) -substituted-N² -arylsulfonyl-L-argininamides (XV) starting materials can be prepared by condensing an N^(G) -substituted-N² -substituted L-arginine (III) (generally the N^(G) -substituent is nitro or acyl, and the N² -substituent is a protective group for the amino group, such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a corresponding amino acid derivative (IV), selectively removing only the N² -substituent of an N^(G) -substituted-N² -substituted L-argininamide (V) by means of catalytic hydrogenolysis or acidolysis, and then condensing the thus obtained N^(G) -substituted-L-argininamide (XIV) with an arylsulfonyl halide (VII), preferably a chloride in the presence of a base in a solvent. These reaction conditions are as described above in the condensation of an L-argininamide with an arylsulfonyl halide, and the removal of the N^(G) -substituent from and N^(G) -substituted-N² -arylsulfonyl-L-argininamide.

(c) Condensation of an N² -arylsulfonyl-L-arginyl halide with an amino acid derivative

This process may be illustrated as follows: ##STR472## In the above formulas, R, Ar and X are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by the condensation of an N² -arylsulfonyl-L-arginyl halide (XVII), preferably a chloride with at least an equimolar amount of an amino acid derivative (IV). The condensation reaction can be carried out without an added solvent in the presence of a base. However, satisfactory results will be obtained with the use of a solvent such as basic solvents (dimethylformamide, dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.).

The amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of the N² -arylsulfonyl-L-arginyl halide (XVII).

Preferred condensation reaction temperatures are in the range of from -10° C to room temperature. The reaction time is not critical, but varies with the amino acid derivative (IV) employed. In general, a period of from 5 minutes to 10 hours is operable. The obtained N² -arylsulfonyl-L-argininamide can be isolated and purified in the same manner as described above.

The N² -arylsulfonyl-L-arginyl halide (XVII) starting materials required for the condensation reaction can be prepared by reacting an N² -arylsulfonyl-L-arginine (XVI) with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorous oxychloride, phosphorus trichloride, phosphorous pentachloride or phosphorus tribromide. The halogenation can be carried out with or without an added solvent. The preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxane.

The amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of the N² -arylsulfonyl-L-arginine (XVI).

Preferred reaction temperatures are in the range of -10° C to room temperature. The reaction time is not critical, but varies with the halogenating agent and reaction temperature. In general, a period of 15 minutes to 5 hours is operable.

The N² -arylsulfonyl-arginines (XVI) which are the starting materials for the preparation of the N² -arylsulfonyl-L-arginyl halides (XVII) can be prepared by the condensation of L-arginine (II) with a substantially equimolar amount of arylsulfonyl halides (VII), by a method similar to that described in the condensation of an L-argininamide with an arylsulfonyl halide.

(d) Guanidylation of an N² -arylsulfonyl-L-ornithinamide or an acid addition salt thereof.

This process may be illustrated as follows: ##STR473## In the above formulas, R and Ar are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by guanidylating an N² -arylsulfonyl-L-ornithinamide (XVIII) with an ordinary guanidylating agent such as an O-alkylisourea, S-alkylisothiourea, 1-guanyl- 3,5-dimethylpyrazole or carbodiimide. The preferred guanidylating agents are the O-alkylisourea and the S-alkylisothiourea.

The guanidylation of the N² -arylsulfonyl-L-ornithinamide (XVIII) with the O-alkylisourea or S-alkylisothiourea is generally effected in a solvent in the presence of a base at a temperature of from 0° C to the boiling temperature of the solvent for a period of from 30 minutes to 50 hours.

Examples of the preferred bases are triethylamine, pyridine, sodium hydroxide and sodium methoxide. The base is used in an amount of 0.01 to 0.1 equivalent to the N² -arylsulfonyl-L-ornithinamide.

Examples of the preferred solvents are water, water-ethanol and water-dioxane.

After the reaction is complete, the N² -arylsulfonyl-L-ar gininamide (I) is isolated by evaporation of the solvent followed by removal of the excess base and the formed salt by a water wash.

It is well recognized in the art that an ester derivative of the N² -arylsulfonyl-L-argininamide (I) wherein R₃ is alkyl, aralkyl, aryl or 5-indanyl, can be prepared from a carboxylic acid derivative of the N² -arylsulfonyl-L-argininamide wherein R₃ is hydrogen, by the conventional esterification methods well known to those skilled in the art. It is also well recognized in the art that the carboxylic acid derivative can be prepared from the ester derivative by the conventional hydrolysis or acidolysis methods. The conditions under which esterification, hydrolysis or acidolysis would be carried out will be each apparent to those skilled in the art.

The N² -arylsulfonyl-L-argininamide (I) of this invention forms acid addition salts with any of a variety of inorganic and organic acids. Some of the N² -arylsulfonyl-L-argininamides containing a free carboxyl group, wherein R₃ is hydrogen, forms salts with any of a variety of inorganic and organic bases.

The product of the reactions described above can be isolated in the free form or in the form of salts. In addition, the product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like. In a similar manner, the product can be obtained as pharmaceutically acceptable salts by reacting one of the free carboxylic acids with a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, N-ethylpiperidine or the like.

Likewise, treatment of the slats with a base or acid results in a regeneration of the free amide.

As stated above, the N² -arylsulfonyl-L-argininamides, and the salts thereof of this invention are characterized by their highly specific inhibitory activity in mammals against thrombin as well as by their substantial lack of toxicity, and therefore these compounds are useful in the determination of thrombin in blood as diagonostic reagents, and/or for the medical control or prevention of thrombosis.

The compounds of this invention are also useful as an inhibitor of platelet aggregation.

The antithrombotic activity of the N² -arylsulfonyl-L-argininamide of this invention was compared with that of a known antithrombotic agent, N² -(p-tolylsulfonyl)-L-arginine methyl ester, by determining the fibrinogen coagulation time. The measurement of the fibrinogen coagulation time was conducted as follows:

An 0.8 ml aliquot of a fibrinogen solution, which had been prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied by Armour Inc. in 40 ml of a borate saline buffer (pH 7.4), was mixed with 0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solution in the same buffer, and 0.1 ml of a thrombin solution (5 units/ml) supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutions in an ice bath.

Immediately after mixing, the reaction mixture was transferred from the ice bath to a bath maintained at 25° C. Coagulation times were taken as the period between the time of transference to the 25° C bath and the time of the first appearance of fibrin threads. In the cases where no drug samples were added, the coagulation time was 50-55 seconds. The experimental results are summarized in Table 1. The term "concentration required to prolong the coagulation time by a factor of two" is the concentration of an active ingredient required to prolong the normal coagulation time 50-55 seconds to 100-110 seconds.

The concentration required to prolong the coagulation time by a factor of two for the known antithrombotic agent, N² -(p-tolylsulfonyl)-L-arginine methyl ester, was 1,100μm. The inhibitors are shown in Table 1 by indicating R and Ar in the formula (I) and the addition moiety.

When a solution containing an N² -arylsulfonyl-L-argininamide of this invention was administered intravenously into animal bodies, the high antithrombotic activity in the circulating blood was maintained for from one to three hours. The halflife for decay of the anti-thrombotic compounds of this invention in circulating blood was shown to be approximately 60 minutes; the physiological conditions of the host animals (rat, rabbit, dog and chimpanzee) were well maintained. The experimental decrease of fibrinogen in animals caused by infusion of thrombin was satisfactorily controlled by simultaneous infusion of the compounds of this invention.

The acute toxicity values (LD₅₀) determined by intraperitoneal administration of substances of formula (I) in mice (male, 20 g) range from about 1,000 to 10,000 milligrams per kilogram of body weight.

Representative LD₅₀ values for the compounds of this invention are shown in the following Table.

    ______________________________________                                         Compound                LD.sub.50 (mg/kg)                                      ______________________________________                                         N.sup.2 -(7-methyl-2-naphthylsulfonyl)-L-                                      arginyl-N-butylglycine  >1,500                                                 N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-(2-methoxyethyl)glycine                                                                      1,900-2,400                                            N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-(2-ethoxyethyl)-β-alanine                                                               660-1,000                                              N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-(2-methoxyethyl)glycine                                                                      660-1,000                                              N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-L                                                              2,000                                                  arginyl-N-(2-methoxyethyl)glycine                                              N.sup.2 -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-                                                      >1,500                                                 L-arginyl-N-(2-methoxyethyl)glycine                                            N.sup.2 -(6,7-dimethyl-1-naphthylsulfonyl)-L-                                                          >1,500                                                 arginyl-N-(2-methoxyethyl)glycine                                              N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                 arginyl-N-(2-ethylthioethyl)glycine                                                                    >1,000                                                 N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                                         >1,000                                                 arginyl-N-benzylglycine                                                        N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-L-                                                         >1,000                                                 arginyl-N-benzylglycine                                                        N.sup.2 -(5-methoxy-1-naphthylsulfonyl)-L-                                                             >1,000                                                 arginyl-N-benzylglycine                                                        N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                                         >1,500                                                 arginyl-N-phenethylglycine                                                     N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                                         >1,500                                                 arginyl-N-cyclohexylglycine                                                    N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                                         >1,500                                                 arginyl-N-cyclohexylmethylglycine                                              N.sup.2 -(7-methyl-2-naphthylsulfonyl)-L-                                                              600                                                    arginyl-N-tetrahydrofurfurylglycine                                            N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                                         620                                                    arginyl-N-tetrahydrofurfurylglycine                                            N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                                         >1,500                                                 arginyl-N-butylalanine                                                         N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-L-                                                         >1,500                                                 arginyl-N-cyclohexylmethylalanine                                              1-[N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                                                      1,500                                                  arginyl]-2-piperidinecarboxylic acid                                           Ethyl[1-N.sup.2 (7-methoxy-2-naphthylsulfonyl)-                                                        670-1,000                                              L-arginyl]-4-methyl-2-piperidinecarboxylate                                    1-[N.sup.2 (4,6-dimethoxy-2-naphthylsulfonyl)-                                 L-arginyl]-4-methyl-2-piperidinecarboxylic                                                             670-1,000                                              acid                                                                           1-[N.sup.2 -(1-napthylsulfonyl)-L-arginyl]-4-                                                          700-1,000                                              methyl-2-piperidinecarboxylic acid                                             1-[N.sup.2 -(5-dimethylamino-1-naphthylsulfonyl)-                                                      700-1,000                                              L-arginyl]-2-piperidinecarboxylic acid                                         4-[N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-L-                                                          >1,000                                                 arginyl]-3-morpholincarboxylic acid                                            2-[N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                              arginyl]-1,2,3,4-tetrahydroisoquinoline-3-                                                             >1,000                                                 carboxylic acid                                                                2-[N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                              arginyl]-1-isoindolinecarboxylic acid                                                                  >1,000                                                 ______________________________________                                    

On the other hand, LD₅₀ values for N² -dansyl-N-butyl-L-argininamide and N² -dansyl-N-methyl-N-butyl-L-argininamide are 75 and 70 milligrams per kilogram, respectively. The therapeutic agents of this invention may be administered to mammals, including humans alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.

For example, the compounds may be injected parenterally, that is, intramuscularly, intravenously or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may be administered sublingually in the form of troches or lonzenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The compounds may be administered orally in the form of solutions which may contain coloring and flavoring agents. Physicians will determine the dosage of the present therapeutic agents which will be most suitable, and dosages vary with the mode of administration and the particular compound chosen. In addition, the dosage will vary with the particular patient under treatment. When the composition is administered orally, a larger quantity of the active agent will be required to produce the same effect as caused with a smaller quantity given parenterally.

The therapeutic dosage is generally 10-50 mg/kg of active ingredient parenterally, 10-500 mg/kg orally per day. Having generally described the invention, a more complete understanding can be obtained by reference to certain specific examples, which are included for purposes of illustration only and are not intended to be limiting unless otherwise specified.

It is to be understood that the present invention includes pharmaceutical compositions containing a compound of the invention as an active ingredient. Such compositions may be in the forms described above.

In particular, the invention includes such compositions in unit dose form.

EXAMPLE 1

(A) Ethyl 1-[N^(G) -nitro-N² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate. To a well stirred solution of 2.05 g of ethyl 1-(N^(G) -nitro-L-arginyl)-4-methyl-2-piperidinecarboxylate hydrochloride and 1.26 g of NaHCO₃ in 10 ml of water and 40 ml of dioxane, was added in portions 2.2 g of 3-cyclohexyl-4-methoxybenzenesulfonyl chloride, while maintaining the temperature at 0° C. The reaction mixture was stirred overnight at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was taken up in 50 ml of ethyl acetate, and the ethyl acetate solution was washed consecutively with 10% citric acid, saturated NaCl, saturated NaHCO₃ and saturated NaCl solutions. The ethyl acetate solution was evaporated and the residue was chromatograhed on silica gel packed in chloroform, and eluted from chloroform containing 3% methanol. The main fraction was evaporated to dryness to give 2.6 g of ethyl 1-[N^(G) -nitro-N² -(3-cyclohexyl- 4-methoxybenzenesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate. I.R. (KBr): 3400, 1735, 1635, 1250 (cm⁻¹)

(B) Ethyl 1-[N² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarobylate acetate.

To a solution of 2.6 g of ethyl 1-[N^(G) -nitro-N² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in 40 ml of ethanol, 10 ml of water and 20 ml of acetic acid, was added 0.5 g of palladium black and then the mixture was shaken in a hydrogen atmosphere for 15 hours at room temperature. The solution was filtered to remove the catalyst and evaporated to give an oily product.

Reprecipitation with ethanol-diethyl ether gave 2.4 g of ethyl 1-[N² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate acetate.

(C) 1-[N² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid.

A solution of 2.4 g of ethyl 1-[N² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate acetate in 10 ml of ethanol and 10 ml of N-NaOH solution was stirred overnight at room temperature. Then, the reaction mixture was concentrated and dissolved in 10 ml of water. The solution was neutralized with 2N-HCl solution to give a white gummy precipitate which was dissolved in 150 ml of chloroform. The chloroform solution was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.52 g of 1-[N² -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid as an amorphous solid. I.R. (KBr): 3350, 2920, 1620, 1250 cm⁻¹.

Analysis-Calcd. for C₂₆ H₄₁ O₆ N₅ S (percent): C, 56.60; H, 7.49; N, 12.70. Found (percent): C, 56.51; H, 7.53; N, 12.68.

EXAMPLE 2

(A) N² -(2-phenoxathiinylsulfonyl)-L-arginyl chloride hydrochloride.

A suspension of 3 g of N² -(2-phenoxathiinylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N² -(2-phenoxathiinylsulfonyl)-L-arginyl chloride hydrochloride.

(B) Ethyl 1-[N² -(2-phenoxathiinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate.

To a stirred solution of 3.6 g of ethyl 4-methyl-2-piperidinecarboxylate in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N² -(2-phenoxathiinylsulfonyl)-L-arginyl chloride hydrochloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 50ml of chloroform was added and the chloroform solution was washed twice with 25 ml of saturated sodium chloride solution, dried over Na₂ SO₄ and evaporated in vacuo. The oily residue was washed with ether to give 3.5 g of powdery ethyl 1-[N² -(2-phenoxathiinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate.

(C) 1-[N² -(2-phenoxathiinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid.

A solution of 3.5 g of ethyl 1-[N² -(2-phenoxathiinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in 15 ml of methanol and 10 ml of 2N-NaOH solution was warmed to 30° C and held at that temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H⁺ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1:4) and eluted with ethanol-water-NH₄ OH (10:9:1). The main fraction was evaporated to dryness and washed with ether to give 1.0 g of 1-[N² -(2-phenoxathiinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid as an amorphous solid. I.R. (KBr): 3400, 1625, 1460, 1165 cm⁻¹.

Analysis-calcd. for C₂₅ h₃₁ O₆ N₅ S₂ (percent): C, 53.46; H, 5.56; N, 12.47. Found (percent): C, 53.55; H, 5.63; N, 12.51.

Various other N² -arylsulfonyl-L-argininamides or acid addition salts thereof were synthesized in accordance with the procedures of the above examples, and the test results are summarized in Table 2.

                                      Table 2                                      __________________________________________________________________________      ##STR474##                        Concentration required to prolong the                                          coagulation time by a                                                                  Prepa- ration process                                                              Phys- ical                                                                         Elemental analysis                                                            Upper:                                                                                   I.R.lated          Sample                       Addition                                                                             factor of two                                                                         (Ex.                                                                               proper-                                                                            Lower:                                                                                  (KBr)               No.                                                                               Ar              R         moiety                                                                               (μ M)                                                                              No.)                                                                               ties                                                                               C  H  N  (cm.sup.-1)         __________________________________________________________________________         ##STR475##                                                                                     ##STR476##     0.1    1       56.60 56.51                                                                       7.49 7.53                                                                         12.70                                                                             3,350 2,920                                                                    1,620 1,250         2                                                                                  ##STR477##                                                                                     ##STR478##            1       55.84 56.07                                                                       7.31 7.46                                                                         13.03 13.08                                                                       3,350 1,620                                                                    1,380 1,150         3                                                                                  ##STR479##     "                      1       57.23 57.15                                                                       6.47 6.70                                                                         12.84 12.75                                                                       3,350 1,620                                                                    1,260 1,155         4                                                                                  ##STR480##     "               0.1    2       53.46 53.55                                                                       5.56 5.63                                                                         12.47 12.51                                                                       3,400 1,625                                                                    1,460 1,165         5                                                                                  ##STR481##     "                      1       58.23 58.08                                                                       6.45 6.51                                                                         13.58 13.62                                                                       3,375  1,620                                                                   1,385 1,160         6                                                                                  ##STR482##     "                      1       59.18 59.08                                                                       6.30 6.52                                                                         13.27 13.36                                                                       3,350 16,10                                                                    1,140               7                                                                                  ##STR483##                                                                                     ##STR484##            1       51.77 52.05                                                                       5.10 5.08                                                                         13.13 12.98                                                                       3,400 1,630                                                                    1,160               8                                                                                  ##STR485##                                                                                     ##STR486##            1       53.65 53.88                                                                       5.22 5.36                                                                         12.51 12.40                                                                       3,400 1,710                                                                    1,630               9                                                                                  ##STR487##                                                                                     ##STR488##            1       53.86 54.08                                                                       6.16                                                                              17.13 17.39                                                                       3,375 1,620                                                                    1,460 1,290         10                                                                                 ##STR489##                                                                                     ##STR490##            1       57.32 57.27                                                                       7.66 7.68                                                                         12.38 12.45                                                                       3,400 1,620                                                                    1,250               11 "                                                                                               ##STR491##            1       56.60 56.82                                                                       7.49 7.36                                                                         12.70 12.86                                                                       3,400 1,620                                                                    1,140               12                                                                                 ##STR492##                                                                                     ##STR493##                                                                              CH.sub.3 COOH                                                                               1       56.85 56.69                                                                       6.84 7.15                                                                         11.05 10.88                                                                       3,400 1,740                                                                    1,635               __________________________________________________________________________

PREPARATION A 2-Piperidinecarboxylic acids and esters thereof

(A) 4-methyl-2-piperidinecarbonitrile

To 500 g of 10% sodium hypochlorite solution cooled in an ice bath, there was added dropwise a solution of 33.6 g (0.21 mole) of 4-methylpiperidine acetate in 10 ml of water over a period of 1 hour. At the end of this period, the reaction product was extracted twice with 500 ml of ethyl ether and dried over anhydrous sodium sulfate. After evaporation of ethyl ether, the residue was added dropwise to a solution of 11.8 g (0.21 mole) of potassium hydroxide in 100 ml of 96% ethanol under reflux.

Refluxing was continued for an additional 10 minutes. Ethanol was evaporated and the residue was dissolved into 50 ml of 2N sodium hydroxide solution and then extracted with ether.

The ether layer was dried over anhydrous sodium sulfate and then ether evaporated. The residue was added to an ice-cooled solution of 27 g (1 mole) of hydrogen cyanide and 25 ml of concentrated hydrochloric acid in 300 ml of water. The solution was stirred at a temperature of 10 to 20° C for 4 hours and thereafter made basic by the addition of solid sodium hydroxide. The reaction product was extracted with ether, dried over anhydrous sodium sulfate and then distilled under reduced pressure to give 17 g (66%) of 4-methyl-2-piperidinecarbonitrile, B.P. 96-97° C/10 mmHg.

The following 2-piperidinecarbonitriles not previously reported in the chemical literature were synthesized by the aforementioned procedure which is essentially that as taught by Grundon et al., J. Chem. Soc., 1963, 3898, Grundon et al., J. Chem. Soc., 1964, 2448, R. Bonnett et al., J. Chem. Soc., 1959, 2092 and H. Bohme et al., Ber., 92, 1613 (1959).

    ______________________________________                                          ##STR494##                                                                    No.      R.sub.2       B.P.                                                    ______________________________________                                         1        4-CH.sub.2 CH.sub.3                                                                          105 - 106° C/9 mmHg.                             2        4-CH.sub.2 CH.sub.2 CH.sub.3                                                                 116° C/8 mmHg.                                             ##STR495##   104° C/4 mmHg.                                   4        2-CH.sub.3                                                            ______________________________________                                    

(B) 4-Methyl-2-piperidinecarboxylic acid hydrochloride

A solution of 16 g of 4-methyl-2-piperidinecarbonitrile in 250 ml of 6N hydrochloric acid was refluxed for 6 hours. After evaporation of the solvent, the residue was recrystallized from water to give 13 g of 4-methyl-2-piperidinecarboxylic acid hydrochloride.

(C) Ethyl 4-methyl-2-piperidinecarboxylate

a solution of 13 g (0.072 mole) of 4-methyl-2-piperidinecarboxylic acid hydrochloride and 50 ml of thionyl chloride in 300 ml of ethanol was refluxed for 4 hours. At the end of this period, the solvent was evaporated under reduced pressure, and the residue was extracted with a solution of chloroform and saturated potassium carbonate solution.

The chloroform layer was dried over anhydrous sodium sulfate and then chloroform was evaporated. Distillation of the residue gave 7.4 g (60%) of ethyl 4-methyl-2-piperidinecarboxylate, B.P. 76-77° C/3 mmHg.

(D) Benzyl 4-methyl-2-piperidinecarboxylate p-toluenesulfonate

A solution of 20 g (0.112 mole) of 4-methyl-2-piperidinecarboxylic acid hydrochloride, 24 g (0.224 mole) of benzyl alcohol and 25.6 g (0.134 mole) of p-toluenesulfonic acid monohydrate in 100 ml of benzene was refluxed for 5 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solvent was distilled off, and the residue was washed with ether-n-hexane and recrystallized to give 10 g (22%) of benzyl 4-methyl-2-piperidinecarboxylate p-toluenesulfonate, M.P. 160-163° C.

The following 2-piperidinecarboxylates not previously reported in the chemical literature were synthesized by the aforementioned procedure.

    ______________________________________                                          ##STR496##                                                                                       Addition                                                    No.   R.sub.2      moiety    B.P.                                              ______________________________________                                         1     4-CH.sub.2 CH.sub.3                                                                         --        82-4° C/3.5 mmHg                           2     4-CH.sub.2 CH.sub.2 CH.sub.3                                                                HCl                                                                ##STR497##  --        95-6° C/2 mmHg                             4     2-CH.sub.3   --        57° C/3 mmHg                               ______________________________________                                     

What is claimed as new and desired to be secured by Letters Patent of the United States is:
 1. An N² -arylsulfonyl-L-argininamide having the formula (I): ##STR498## or a pharmaceutically acceptable salt thereof, wherein R is ##STR499## wherein R₁ is -COOR₃ wherein R₃ is hydrogen, C₁ -C₁₀ alkyl, C₆ -C₁₀ aryl, C₇ -Chd 12 aralkyl or 5-indanyl; each R₂ independently is hydrogen, C₁ -C₁₀ alkyl, phenyl, C₁ -C₅ alkoxy, C₂ -C₆ alkoxycarbonyl, or carboxy; n is an integer of 1 to 4, R₁ is substituted into the piperidine ring at the 2 or 3 position; and R₂ is substituted into the piperidine ring at the 2, 3, 4, 5 or 6 position;and Ar is naphthyl substituted with at least one substituent selected from the group consisting of halo, nitrom cyano, hydroxy, C₁ -C₁₀ alkyl and C₂ -c₂₀ dialkylamino, and at least one substituent selected from the group consisting of C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₀ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy, or mixtures thereof; naphthyl substituted with at least one C₁ -C₅ alkoxy and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof; naphthyl substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;
 5. 6,7,8-tetrahydronaphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof;a C₉ -C₁₆ cycloalkylphenyl, C₁₀ -C₁₈ cycloalkylalkylphenyl, C₉ -C₁₆ cycloalkoxyphenyl, C₉ -C₁₆ cycloalkylthiophenyl, C₇ -C₁₂ aralkyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 1,2-methylenedioxphenyl, 1,2-ethylenedioxyphenyl, chromanyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl, 1,2-trimethylenedioxyphenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl group, any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀, N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl, oxo and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof; a naphthoquinonyl, anthryl phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, as-indacenyl, s-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo(b) thienyl, isobenzothienyl, oxanthrenyl, thianthrenyl, dibenzofuranyl, dibenzothienyl, phenoxathiinyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl group, any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxyalkyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof, a phenyl which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, C₂ -C₂₀ dialkylamino, sulfoamino, carbamoyl, C₃ -C₁₀ N,N-dialkylcarbamoyl, amino, C₁ -C₁₀ alkylamino, mercapto, C₁ -C₁₀ alkylthio, C₇ -C₁₂ aralkyl, carboxyl, C₂ -C₁₀ alkoxycarbonyl, C₂ -C₁₀ carboxylakyl, C₁ -C₁₀ acylamino, C₂ -C₁₀ alkylcarbonyl, C₁ -C₁₀ hydroxyalkyl, C₁ -C₁₀ haloalkyl and phenyl optionally substituted with at least one hydroxy, C₁ -C₅ alkoxy or mixtures thereof.
 2. The compound of claim 1, wherein said Ar group is substituted with at least one C₁ -C₅ alkoxy, C₁ -C₅ alkyl group or mixtures thereof.
 3. The compound of claim 2, wherein said Ar group is substituted with at least one C₁ -C₅ alkoxy group.
 4. A method of inhibiting activity and suppressing activation of thrombin in vivo which comprises administering to a mammal a pharmaceuticaly effective amount of a compound of claim
 1. 5. A method of inhibiting activity and suppressing activation of thrombin in vivo which comprises administering to a mammal a pharmaceutically effective amount of a compound of claim
 2. 